Cancer cells exploit the molecular machinery normally used for cell growth and differentiation during development. The primary cilium, a cell surface structure that projects into the extracellular environment and interprets intercellular signals, is potentially important for cancer initiation and progression. Hedgehog signals act through primary cilia to regulate patterning and growth during development and misregulation of Hedgehog signaling is implicated in many diseases including pancreatic ductal adenocarcinoma, an extremely lethal form of cancer. Hedgehog signals are produced by many pancreatic tumors and treatment with Hedgehog inhibitors slows tumor growth. Recent studies indicate that Hh signals sent from tumors to surrounding stromal cells are important for promoting tumor growth. This project aims to investigate the role of the primary cilium and Hedgehog signaling in pancreatic cancer by addressing two questions: (1) are cilia required for tumor growth, either in cancer cells or their supporting cells? and (2) are Hedgehog signals transduced through primary cilia in cancer pathogenesis? Using targeted knockdown and gene trap technology in mouse models of pancreatic cancer, cilia will be deleted from either cancer cells or the supporting mesenchyme and effects on tumor histology, growth and vascularization will be observed over time. To determine if cilia are required in Hedgehog signal transduction during tumorigenesis, changes in Hedgehog target gene expression will be monitored upon deletion of stromal cilia. To elucidate the mechanism by which cilia participate in Hedgehog signal transduction, activated alleles of Hedgehog signal transduction proteins will be introduced into the tumor cells or stromal support cells and tested to see whether they require or bypass the reliance on primary cilia. Examining ciliary function in pancreatic cancer will provide cell biological insights into signal transduction and tumorigenesis and may lead to the development of novel cancer therapies. PUBLIC HEALTH RELEVANCE: Cancer is among the leading causes of death worldwide and yet our understanding of pathogenesis and treatment is limited. Pancreatic cancer is a highly aggressive form of cancer with an extremely low survival rate. Studying the mechanisms that control pancreatic tumor formation and progression will broaden our understanding of tumorigenesis and may provide new targets for cancer therapies.